Progress in cardiovascular research has made it possible to reduce the incidence of heart attacks in patients principally by reducing the risk factors for atherosclerosis, such as hypercholesterolemia, smoking, and hypertension. It is known that the development of a heart attack can be stopped by administering tissue-type plasminogen activator (t-PA), which dissolves the thrombus in the coronary artery. Recently, the cloning and production of t-PA by recombinant DNA techniques has made it possible to produce t-PA in unlimited quantities.
For prevention of heart attacks in patients who have developed coronary atherosclerosis, there are, however, only surgical methods available. Several important new techniques have been developed for surgical therapy. In particular, angioplastic procedures using balloon catheters, and more recently lasers, have made it possible to treat patients with less severe symptoms, where coronary bypass surgery is not warranted, and also patients whose general condition is too poor to permit major surgery.
All manipulations of major blood-vessels, be it conventional surgery or angioplastic procedures, are, however, hampered by the frequent occurrence of intimal hyperplasia leading to restenosis of the artery. For example, approximately 30% of all patients who undergo percutaneous transluminal coronary angioplasty at Sahlgren's Hospital, Gothenburg, Sweden, develop intimal lesions that give rise to ischemic symptoms.
The problem is also observed after conventional vascular surgery. Reconstructive surgery of the arteries, that supply the lower extremities with blood is followed by a recurrence of the ischemic symptoms, due to intimal lesions, in 50% of all cases. (See Rutherford R. (ed). Vascular Surgery. Ch. 58. 2nd ed., Saunders, 1984.) Similarly, approximately 20% of all patients who undergo carotid endarterectomy develop intimal hyperplasia. Similar results have been reported from several other treatment centers. Intimal hyperplasia is also often observed in connection with coronary bypass surgery. Postoperative and "postangioplastic" intimal hyperplasia is therefore today a major problem in clinical cardiology, heart surgery and vascular surgery.
For example, many patients with angina pectoris will have to undergo repeated angioplastic procedures, and coronary bypass surgery may eventually have to be performed. It is clear that if one could stop the development of intimal hyperplasia, it would be possible to save patients from muc pain and suffering and also to reduce the costs of treatment substantially.
The mechanisms underlying intimal cell proliferation have been meticulously studied by vascular biologists. It is known that mechanical injury to the artery results in migration-of medial smooth muscle cells into the intima. Once in the intima, the cells begin to proliferate, forming an intimal lesion that persists for months. (See Schwartz S. M., Campbell GR, Campbell J. H. Circ Res 58:427, 1986.) Reendothelialization of the surface seems to be important for regression of the lesion, and both the endothelial area involved and the amount of damage to subendothelial structures are important for the progression of the lesion.
The proliferation of vascular smooth muscle cells is probably controlled by growth factors that either circulate in the blood, such as insulin, or are released from cells, such as the platelet-derived growth factor. The latter factor is synthesized not only by megakaryocytes but also by monocytes and endothelial cells (see Ross R. New Engl J Med 314:488, 1986 and Ross R., Raines E. W., Bowen-Pope D. F. Cell 1986:46:155-169), and this implies that inflammatory cells might participate in the growth regulation of the vessel wall.
Much less is known about growth-inhibiting factors for smooth muscle cells. Heparin administered pharmacologically inhibits smooth muscle profileration (see Clowes A. W, Karnovsky M. J. Nature 265:625, 1977), and it has been suggested that endogenous heparin-like substances may be involved in physiologic growth control. It should, however, be noted that all patients who undergo angioplastic and surgical treatment are under heparin therapy, and yet develop significant intimal stenosis.
Recent immunocytochemical studies using cell typespecific monoclonal antibodies have shown that monocyte-derived macrophages are present in large numbers in the atherosclerotic plaque. (See Vedeler C. A., Nyland H., Matre R.: In situ characterization of the foam cells in early human atherosclerotic lesions. Acta Pathol Microbiol Immunol Scand (C) 1984:92:133-137, Aqel N. M., Ball R. Y., Waldman H, Mitchinson M. J.: Monocytic origin of foam cells in human atherosclerotic plaques. Atherosclerosis 1984:53:265-271, Jonasson L., Holm J., Skalli O., Bondjers G., Hansson G. K.: Regional accumulations of T cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis 1986:6:131-140 and Gown A. M., Tsukada T., Ross R.: Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol 1986:125:191-207.) They are, however, not the only blood-borne cells that can be found in the arterial wall under pathological circumstances. T lymphocytes constitute one fifth of the cell population in the fibrous cap of the human atherosclerotic plaque (see Jonasson et al, Atherosclerosis 1986:6:131-140), and they can also be observed in experimental models of vascular injury. (See Jonasson L., Holm J., Hansson G. K.: Smooth muscle cells express Ia antigens during arterial response to injury. Lab Invest 1988:58:310-315.)
Immunocytochemical data suggest that T lymphocytes can modulate the growth properties and other functions of smooth muscle cells. In atherosclerotic plaques, where T lymphocytes are abundant, many smooth muscle cells express class II major histocompatibility complex antigens (Ia antigens). On the other hand smooth muscle cells lack Ia antigens in nonatherosclerotic, normal arteries. (See Jonasson L., Holm J., Skalli O., Gabbiani G., Hansson G. K.: Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest 1985:76:125-131 and Hansson G. K., Jonasson L., Holm J., Claesson-Welsh L. Class II MHC antigen expression in the atherosclerotic plaque; smooth muscle cells express HLA-DR, HLA-DQ, and the invariant gamma chain. Clin exp Immunol 1986:64:261-268.) It has been shown that Ia antigens appear on smooth muscle cells during the arterial response to injury in rats, but there is no prior work showing or suggesting a relation between Ia antigens and vascular stenosis.
These antigens play a basic role in the presentation of foreign antigens to T lymphocytes. Their expression by macrophages, endothelial cells, and several other cell types is induced by gamma-interferon secreted by activated T lymphocytes. (See Pober J. S, Gimbrone M. A., Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K.A.: Ia expression by vascular endothelium is inducible by activated T cells and by human gamma-interferon. J Exp Med 1983:157: 1339-1353 and Unanue E. R., Allen P. M.: Comment on the finding of Ia expression in non-lymphoid cells. Lab Invest 1986: 55:123-125.)
Alfa- and beta-type interferons, which are produced by leukocytes, fibroblasts, and other cell types, are known to inhibit the proliferation of certain cell types. Gamma-interferon is released by activated T lymphocytes, and it also has been shown to inhibit proliferation when conditioned media or purified preparations are added to culture cells of various types, such as mammary gland cells and fibroblasts. (See Rubin B. Y., Gupta S. L.: Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc Natl Acad Sci USA 1980: 77:5928-5932, Blalock J. E., Georgiades J. A., Langford N. F., Johnson H. M.: Purified human immune interferon has more potent anticellular activity than fibroblast or leukocyte interferon. Cell Immunol 1980:49:390-394 and Wahl S. M., Galtely C. L.: Modulation of fibroblast growth by a lymphokine of human T cell and continuous T cell line origin. J Immunol 1983:130: 1226-1230.) However, it has been questioned whether this effect might be due to contaminations of the preparations with lymphotoxin (tumornecrosis factor) rather than an inhibitory effect of gamma-interferon itself.
Summing up it would be advantageous to be able to treat vascular stenosis and related disorders by use of preparations that inhibit growth of smooth muscle cells.